82 Juvenile dermatomyositis with early-onset anti-MDA 5 antibodies: a case report

Abstract Background Juvenile dermatomyositis (JDM) is a very rare inflammatory myopathy with an approximate incidence of 2–4 per million. The discovery of specific circulating autoantibodies present in about 60% of cases has allowed them to be classified according to their clinical and immunological expressions and their therapeutic response. Anti-Melanoma differentiation associated gene5 (MDA5) antibodies seem to be correlated with a particular clinical phenotype associating cutaneous, respiratory, and articular involvement and most often sparing the muscles. Observation We report the case of an early-onset anti-MDA 5 JDM in a 27-month-old girl. The first symptoms appeared at the age of 18 months and consisted of a skin rash and muscle weakness complicated 6 months later by generalized oedema. The child received symptomatic treatments without improvement. At 27 months of age, the child worsened and was admitted for respiratory distress. On clinical examination, she presented with fever and general deterioration, respiratory impairment with swallowing problems, skin damage with specific ulcerations, very significant generalized oedema, and severe muscle damage with axial hypotonia and myogenic EMG tracing. The inflammatory workup was positive and the autoimmune workup revealed 1/320 speckled antinuclear antibody (ANA) and positive anti-MDA5 anti bodies. Chest CT scan showed right interstitial lung disease. The diagnosis of anti-MDA5 JDM was retained and the child was treated with corticosteroids pulses associated with immunoglobulins and methotrexate (MTX) leading to a clear improvement. Corticosteroids and MTX were maintained on a long-term basis. Discussion The prevalence of anti-MDA5 anti bodies is variable and depends on ethnic origin (7% in an English cohort vs 38% in the Japanese cohort). These antibodies seem to be specific to a particular phenotype of DM associating skin involvement, interstitial lung disease with little or no muscle involvement. The originality of this observation lies in the early age of onset of JDM and in the fact that it expresses the anti-MDA5 antibodies. The skin and muscle involvement was prominent in our patient, while the pulmonary involvement, although not rapidly progressive, justified the combination of bolus methylprednisolone, MTX and immunoglobulins. Despite the delay in diagnosis, we noted a good therapeutic response and stabilization of the disease. Conclusion Anti-MDA 5 antibodies must be identified as soon as JDM is diagnosed; their presence is a risk factor for severe lung damage, which must be systematically investigated and treated to improve the prognosis.


Background
Juvenile scleroderma includes a range of conditions presenting with skin fibrosis. It's classified into two major categories, localized and systemic. Juvenile localized scleroderma (morphea) is limited to the skin and forms majority of pediatric presentations (>95%). Though rare, juvenile systemic sclerosis involves the skin and other internal organs and is associated with a poorer prognosis. Objective To characterize the clinical profile of two cases of scleroderma at Aga Khan university hospital, Nairobi. Methods Retrospective review of medical records of two patients with Juvenile scleroderma managed at Aga Khan university hospital, Nairobi.

Results
The first patient was a 7-year-old boy presenting with joint pains for 2 months, restricted activities and limping. He also had a non-itchy lesion on the right thigh for about 6 years. On examination, there was an 8 by 18 cm, flat, shiny skin lesion with ill-defined margins and skin thickening around it. There were 2 punched out scars from previous skin biopsy sites with latest biopsy showing atrophic epidermis, dermal collagen homogenization with thick sclerosed fibers in keeping with morphea. Pulmonary function tests revealed mild restrictive lung disease. There were no other systems involved on further evaluation. He was started on weekly methotrexate, daily prednisone, daily folic acid and omeprazole to be followed up in clinic. The second case is a 5-year-old girl who presented with 3-year history of inability to walk. Physical examination revealed areas of skin hypopigmentation and hyperpigmentation on the neck and back with active lesions on the left flank and posterior right leg. She had left lower limb atrophy and extreme wasting of thigh and calf muscles, a contracture of the left knee, ankle and limb length discrepancy. Her investigations revealed positive rheumatoid factor, positive antinuclear antibody (ANA), microcytic hypochromic anaemia and skin biopsy with features of morphea. She received six courses of high dose methyl prednisone over six months, weekly methotrexate, daily folic acid, daily prednisone that was tapered off gradually, calcium supplementation and iron supplementation. In addition, she received isoniazid for tuberculosis prophylaxis with pyridoxine. Her management was multidisciplinary involving orthopedics, physiotherapy, occupational therapy, and dieticians. She developed a new skin lesion on the left forearm about five months after initiation of treatment but no worsening of symptoms or other new lesions thereafter. Conclusion Juvenile scleroderma though rare has a high risk of misdiagnosis with delay in initiation of treatment. It is associated with significant morbidity and early diagnosis, treatment and follow up is imperative for good outcomes. Background RHUPUS syndrome is a rare association with rheumatoid arthritis and systemic lupus erythematosus (SLE) in adult patients. Its pediatric presentation is very rare and underdiagnosed. The mechanism is not well understood yet, but most theories accepted a real overlap between SLE and juvenile idiopathic arthritis. In children. Patients with Rhupus have clinical symptoms of SLE with positive ANA, anti-DNA or anti Sm associated with clinical symptoms of JIA. Objective Illustrate an unusual presentation of lupus in children Methods we present a case of juvenile rhupus syndrome; we describe the clinical presentation, the serological results, the diagnostic criteria for SLE (ACR 1997) and JIA (ILLA 2001) and the treatment installed.

Case reports
We recently diagnosed Rhupus syndrome in an 11-year-old girl who presented with polyarthritis deformans of the bilateral joints of the wrists, hands and feet for 24 months. she also had an onset of profound asthenia, recurrent oral aphtosis and massive hair loss over the past few months. Initial investigation showed anaemia, increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Radiographic examinations showed juxtra-articular osteopenia and chronic synovitis of the wrists. The autoimmune assessment was contributory with a positive rheumatoid factor (RF), antinuclear antibodies (ANA) (1/1000) and positive anti-Sm antibodies. Anticardiolipin and anti-RNP antibodies were negative. Our patient met >4 ACR criteria for SLE classification. She was treated with methotrexate and hydroxychloroquine, under close medical supervision in order to watch for the appearance of other organic damage to lupus disease, in particular renal and neurological. This type of joint damage is considered to be either lupus joint damage, lupus with chronic arthritis, or overlapping lupus with JIA. Children with Rhupus initially present with JIA and later develop lupus. Previous reports have shown female predominance, polyarticular involvement, non-erosive arthritis, and years of diagnostic wandering. Our patient had polyarthritis deformans with a two-year delay in diagnosis of SLE. Conclusion Although rare, the infantile Rhupus syndrome must be evoked in front of a deforming arthropathy. Background Juvenile dermatomyositis (JDM) is a very rare inflammatory myopathy with an approximate incidence of 2-4 per million. The discovery of specific circulating autoantibodies present in about 60% of cases has allowed them to be classified according to their clinical and immunological expressions and their therapeutic response. Anti-Melanoma differentiation associated gene5 (MDA5) antibodies seem to be correlated with a particular clinical phenotype associating cutaneous, respiratory, and articular involvement and most often sparing the muscles.

Observation
We report the case of an early-onset anti-MDA 5 JDM in a 27-monthold girl. The first symptoms appeared at the age of 18 months and consisted of a skin rash and muscle weakness complicated 6 months later by generalized oedema. The child received symptomatic treatments without improvement. At 27 months of age, the child worsened and was admitted for respiratory distress. On clinical examination, she presented with fever and general deterioration, respiratory impairment with swallowing problems, skin damage with specific ulcerations, very significant generalized oedema, and severe muscle damage with axial hypotonia and myogenic EMG tracing. The inflammatory workup was positive and the autoimmune workup revealed 1/320 speckled antinuclear antibody (ANA) and positive anti-MDA5 anti bodies. Chest CT scan showed right interstitial lung disease. The diagnosis of anti-MDA5 JDM was retained and the child was treated with corticosteroids pulses associated with immunoglobulins and methotrexate (MTX) leading to a clear improvement. Corticosteroids and MTX were maintained on a long-term basis.

Discussion
The prevalence of anti-MDA5 anti bodies is variable and depends on ethnic origin (7% in an English cohort vs 38% in the Japanese cohort). These antibodies seem to be specific to a particular phenotype of DM associating skin involvement, interstitial lung disease with little or no muscle involvement. The originality of this observation lies in the early age of onset of JDM and in the fact that it expresses the anti-MDA5 antibodies. The skin and muscle involvement was prominent in our patient, while the pulmonary involvement, although not rapidly progressive, justified the combination of bolus methylprednisolone, MTX and immunoglobulins. Despite the delay in diagnosis, we noted a good therapeutic response and stabilization of the disease. Conclusion Anti-MDA 5 antibodies must be identified as soon as JDM is diagnosed; their presence is a risk factor for severe lung damage,

Background
Wilson's disease (WD) is a rare, recessively inherited disorder of copper metabolism with its accumulation in multiple organs particularly in the liver and brain. Systematic lupus erythematosus (SLE) is an autoimmune disease like Wilson's disease, involves multiple organs and systems. The combination of Wilson's disease and systemic lupus erythematosus (SLE) is not usual apart from iatrogenism. Objectives we present a pediatric case of concurrent Wilson's disease and primary SLE not induced by penicillamine. After extensive research in the literature, this is the only male case described so far. The other seven cases reported are female. Case presentation A previously well 12-year-old boy was admitted to University Hospital Center of Batna (Algeria) with acute haemolysis (pallor, subictereus, and red urine). There was no consanguinity, or family history of note. Physical examination revealed normal development and growth, no fever, no lymphadenopathy, no hepatomegaly and splenomegaly. A complete blood count (CBC) revealed normochromic normocytic anaemia, thrombocytopenia, and leucopenia. His blood biochemistry showed hepatic cytolysis, and hepato-cellular insufficiency. Wilson's disease was suspected because of the combination of the impaired liver function, hemolytic anaemia, and normal alkaline phosphatase levels. Serum ceruloplasmin and copper levels were decreased, while urinary copper was elevated confirming the diagnosis of Wilson's disease. There was no neurological or ophthalmologic involvement. Family investigation revealed Wilson's disease with cirrhosis in a 9year-old brother. The onset of nephrotic syndrome and the presence of inflammatory syndrome cannot be explained by Wilson's disease. The kidney biopsy histopathology revealed nephritis lupus class II (WHO classification). Subsequent serum analysis also revealed positive native anti-DNA and anti-PCNA antibodies verified on a second sample. Based on all the findings, the final diagnosis for this patient was Wilson's disease combined with SLE. We started therapy with bolus of corticosteroids and Cyclophosphamide, relayed by Mycophenolate Moftil and hydroxychloroquine Cooper chelation has also been initiated. Improvement in renal and even hepatic damage was noted. Unfortunately, after two years, the patient presented abnormal movements with dysarthria. Brain MRI showed abnormal signals of the basal ganglia consistent with neurological damage in Wilson's disease. Discussion concomitant SLE and WD without penicillamine treatment is rare (7 cases reported in the literature with 3 children). To our knowledge, this is the first report of an association between Wilson's disease and SLE in male case. For our patient, SLE and Wilson's disease were diagnosed simultaneously as 4 described cases. Wilson's disease was first suspected due to unexplained impaired liver function with hemolytic anaemia. Copper Tests confirming the diagnosis. At that time, there was no neurological or ophthalmological impairment. For this patient, the worsening of the hematological involvement (pancytopenia) in an inflammatory context, with installation of a nephrotic syndrome cannot be explained by Wilson's disease. SLE was evoked despite the fact that it was a child and male. The PBR as well as the immunological workup were in favor of SLE disease. Treatment of SLE improved symptoms but later chelation could not prevent the usual neurologic complication of Wilson's disease at this age. The neurological involvement appeared at the age of 14 as described in the literature with the common sign dysathria, followed by the installation of abnormal movements due to the impairment of the basal ganglia objectived by MRI.

Conclusion
Wilson's disease and SLE not induced by penicillamine can co-exist. As there is no pathophysiological explanation, it's probably a simple fortuitous association.

Athul Kooliyath and Angela Migowa
The Aga Khan University, Nairobi

Background
Methotrexate is an antimetabolite commonly used as a chemotherapeutic and as a steroid sparing agent in multiple rheumatologic conditions. The common side effects are well documented and usually seen in patients receiving high dose therapy and hence more commonly seen in oncology. Here, we discuss a case on methotrexate toxicity in a patient being treated for Takayasu arteritis.

Methods
This was a retrospective case review Results A seventeen-year-old was seen in the rheumatology service with a diagnosis of Takayasu arteritis after being initially worked up due to hypertension. Methotrexate therapy was started at an initial dose of 25 mg to be taken weekly. She was later seen in the pediatric outpatient unit 10 days post initiation of therapy with a history of inability to feed due to oral sores and severe abdominal pain. She also complained of odynophagia and hence had poor oral intake. On further history, it was noted that the patient was taking the medication on a daily basis as opposed to the prescribed weekly regimen. On exam, she was noted to have extensive ulceration of her buccal mucosa, gingiva and tongue. She was also found to have severe epigastric tenderness. Her genital regions were however spared. A diagnosis of methotrexate toxicity was made and she was admitted to the high dependency unit for management. Methotrexate was immediately discontinued and a hyper hydration regimen was initiated with intravenous fluids (125 ml/m 2 /h). Her pain was managed with an intravenous morphine infusion. Particular care was taken to avoid drugs such as proton pump inhibitors (PPIs), non-steroidal antiinflammatory drugs (NSAIDs) and Sulphur containing drugs. A rescue was initiated with 15 mg/m 2 of folinic acid given 6 hourly. The patient made a full recovery and was discharged 4 days later.

Discussion and Conclusions
Methotrexate is a drug with varied and severe adverse effects. Toxicity with methotrexate affects multiple systems and can cause end organ damage. It is therefore of paramount importance to recognize toxicity early and manage appropriately before onset of end organ damage. The above patient was risk of hepatotoxicity, renal toxicity, Neurologic toxicity, methotrexate induced lung injury, hematologic toxicity and hypersensitivity. She developed mucositis as a result of the medication. Enhancing renal elimination of the drug is at the core of management. This can be done with hyperhydration, alkalinisation of urine and avoiding drugs that slow elimination of methotrexate such as PPIs, NSAIDs, tyrosine kinase inhibitors, sulfa drugs and penicillin like drugs. Once end organ damage is established, therapy is supportive and highly dependent on the organ systems involved and the extent of injury. It is necessary for clinicians to be well versed with the adverse effects expected with methotrexate as evidenced by this case for prompt diagnosis and sound management. It is also vital to counsel patients and parents about the medication-correct dosage and timing, expected adverse effects and when to seek medical attention.